Details

Autor(en) / Beteiligte

• Booth, Kevin T.
• Azaiez, Hela
• Kahrizi, Kimia
• Wang, Donghong
• Zhang, Yuzhou
• Frees, Kathy
• Nishimura, Carla
• Najmabadi, Hossein
• Smith, Richard J

Titel

Exonic mutations and exon skipping: Lessons learned from DFNA5

Ist Teil von

• Human mutation, 2018-03, Vol.39 (3), p.433-440

Ort / Verlag

United States: Hindawi Limited

Erscheinungsjahr

2018

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness‐associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5‐related deafness. In five families with postlingual progressive autosomal dominant non‐syndromic hearing loss, we employed two next‐generation sequencing platforms—OtoSCOPE and whole exome sequencing—followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini‐genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5‐related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing. DFNA5‐related hearing loss is caused by skipping of exon 8. Novel and previously described pathogenic variants are shown aligned to DFNA5 exon 8 and its flanking introns, with novel variants on the bottom and previously described variants on the top. The two previously described variants underlined in italics also reported in this study. The predicted binding sites of splicing factors are altered by the novel exonic variants, with values in the parentheses showing the predicted splicing signal for the wild‐type sequence (black) and the mutant sequence (red).